PROJECT SUMMARY As the population continues to age, the incidence of dementia is dramatically increasing, resulting in an urgent need to better understand mechanisms underlying abnormal brain aging and dementia. Alterations in cerebral blood flow homeostasis may pose a risk for accelerating age-related brain injury. Prodromal stages of Alzheimer?s disease (AD) are associated with cerebral blood flow (CBF) reductions in the posterior cortical and lateral temporal regions and tissue atrophy (especially within medial temporal structures, such as the hippocampus). It is not yet clear whether cortical hemodynamic changes and medial temporal atrophy may contribute to cognitive decline through interrelated pathways or whether these early findings represent concomitant yet disparate pathogenic cascades. Animal models suggest cortical hypoperfusion and co- occurring changes to white matter integrity may interrupt cortico-hippocampal projections, leading to hippocampal dysfunction, medial temporal atrophy, and cognitive decline. This F32 proposal will leverage innovative, noninvasive neuroimaging technology to examine such associations among a longitudinal, observational study cohort of older adults free of clinical dementia and stroke at enrollment. CBF and cerebrovascular reactivity (CVR) will be related to baseline cognition and cognitive trajectory over a 3-year follow-up period. The Apolipoprotein E ?4 (APOE4) allele is a well-known genetic susceptibility risk factor for AD, and our preliminary data shows APOE4 carrier status interacts with vascular disease burden on cognitive outcomes. Therefore, potential APOE4 carrier status interactions will be considered when relating CBF and CVR to cognitive outcomes. We will also investigate neurodegenerative markers as potential mediating mechanisms to account for CBF and CVR associations with cognitive outcomes. The proposed study leverages the rich resources of the Vanderbilt Memory & Alzheimer?s Center, the Vanderbilt University Institute of Imaging Science, and the Vanderbilt Institute for Clinical & Translational Research, coupled with an interdisciplinary mentorship team representing experts in geriatric neuropsychology, cerebrovascular disease, hemodynamic imaging, AD biomarkers, and biostatistics. A parallel training plan will ensure the candidate develops essential research skills and knowledge in the study of cerebral hemodynamic factors related to AD pathogenesis and cognitive aging. Collectively, the proposed research and training activities will serve as a springboard for the applicant?s programmatic research career focused on early detection and prevention strategies for AD and unhealthy cognitive aging.